Single-cell analysis reveals the transformation of adipose-derived stromal cells into COL11A1-expressing cancer-associated fibroblasts

AbstractDuring the last ten years, many research results have been referring to a particular type of cancer-associated fibroblasts associated with invasiveness, metastasis and resistance to therapy, characterized by a gene expression signature, identical in multiple types of solid cancer, with prominent presence of collagen COL11A1. Identifying the underlying biological mechanisms responsible for their creation may help towards the identification of drug targets for pan-cancer therapeutics. We have performed an extensive computational analysis of single-cell gene expression data from many cancer types, concluding that these fibroblasts are produced by a transformation of adipose-derived stromal cells naturally occurring in the stromal vascular fraction of the adipose microenvironment. Focusing on a rich pancreatic cancer dataset, we provide a detailed description of the continuous modification of the gene expression profile of the cells as they transition from APOD-expressing adipose-derived stromal cells to COL11A1-expressing cancer-associated fibroblasts, identifying the key genes that participate in this transformation.Statement of significanceThis work provides an explanation to the well-known fact that the adipose microenvironment contributes to cancer progression. It also describes an underlying biological mechanism involving the transformation of adipose-derived stromal cells into COL11A1-expressing cancer-associated fibroblasts, at which point metastasis is imminent, with potential of pan-cancer therapeutics targeting those mechanisms.

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Single-cell analysis reveals the pan-cancer invasiveness-associated transition of adipose-derived stromal cells into COL11A1-expressing cancer-associated fibroblasts

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009228 ◽

2021 ◽

Vol 17 (7) ◽

pp. e1009228

Author(s):

Kaiyi Zhu ◽

Lingyi Cai ◽

Chenqian Cui ◽

Juan R. de los Toyos ◽

Dimitris Anastassiou

Keyword(s):

Gene Expression ◽

Single Cell ◽

Stromal Cells ◽

Expression Profiles ◽

Stromal Vascular Fraction ◽

Gene Expression Signature ◽

Cancer Associated Fibroblasts ◽

Expression Signature ◽

Adipose Derived Stromal Cells ◽

Pan Cancer

During the last ten years, many research results have been referring to a particular type of cancer-associated fibroblasts associated with poor prognosis, invasiveness, metastasis and resistance to therapy in multiple cancer types, characterized by a gene expression signature with prominent presence of genes COL11A1, THBS2 and INHBA. Identifying the underlying biological mechanisms responsible for their creation may facilitate the discovery of targets for potential pan-cancer therapeutics. Using a novel computational approach for single-cell gene expression data analysis identifying the dominant cell populations in a sequence of samples from patients at various stages, we conclude that these fibroblasts are produced by a pan-cancer cellular transition originating from a particular type of adipose-derived stromal cells naturally present in the stromal vascular fraction of normal adipose tissue, having a characteristic gene expression signature. Focusing on a rich pancreatic cancer dataset, we provide a detailed description of the continuous modification of the gene expression profiles of cells as they transition from APOD-expressing adipose-derived stromal cells to COL11A1-expressing cancer-associated fibroblasts, identifying the key genes that participate in this transition. These results also provide an explanation to the well-known fact that the adipose microenvironment contributes to cancer progression.

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Single-Cell Gene Expression Analysis and Evaluation of the Therapeutic Function of Murine Adipose-Derived Stromal Cells (ASCs) from the Subcutaneous and Visceral Compartment

Stem Cells International ◽

10.1155/2018/2183736 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9

Author(s):

Dominik Pförringer ◽

Matthias M. Aitzetmüller ◽

Elizabeth A. Brett ◽

Khosrow S. Houschyar ◽

Richard Schäfer ◽

...

Keyword(s):

Gene Expression ◽

Wound Healing ◽

Single Cell ◽

Stromal Cells ◽

Single Cell Level ◽

Cell Level ◽

Adipose Derived Stromal Cells ◽

Wound Healing Model ◽

Healing Model

Introduction. Adipose-derived stromal cells (ASCs) are a promising resource for wound healing and tissue regeneration because of their multipotent properties and cytokine secretion. ASCs are typically isolated from the subcutaneous fat compartment, but can also be obtained from visceral adipose tissue. The data on their equivalence diverges. The present study analyzes the cell-specific gene expression profiles and functional differences of ASCs derived from the subcutaneous (S-ASCs) and the visceral (V-ASCs) compartment. Material and Methods. Subcutaneous and visceral ASCs were obtained from mouse inguinal fat and omentum. The transcriptional profiles of the ASCs were compared on single-cell level. S-ASCs and V-ASCs were then compared in a murine wound healing model to evaluate their regenerative functionality. Results. On a single-cell level, S-ASCs and V-ASCs displayed distinct transcriptional profiles. Specifically, significant differences were detected in genes associated with neoangiogenesis and tissue remodeling (for example, Ccl2, Hif1α, Fgf7, and Igf). In addition, a different subpopulation ecology could be identified employing a cluster model. Nevertheless, both S-ASCs and V-ASCs induced accelerated healing rates and neoangiogenesis in a mouse wound healing model. Conclusion. With similar therapeutic potential in vivo, the significantly different gene expression patterns of ASCs from the subcutaneous and visceral compartments suggest different signaling pathways underlying their efficacy. This study clearly demonstrates that review of transcriptional results in vivo is advisable to confirm the tentative effect of cell therapies.

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Integrated single‐cell RNA sequencing analyses suggest developmental paths of cancer‐associated fibroblasts with gene expression dynamics

Clinical and Translational Medicine ◽

10.1002/ctm2.487 ◽

2021 ◽

Vol 11 (7) ◽

Author(s):

Hee Chul Chung ◽

Eun Jeong Cho ◽

Hyeonjin Lee ◽

Won‐Kyung Kim ◽

Ji‐Hye Oh ◽

...

Keyword(s):

Gene Expression ◽

Single Cell ◽

Rna Sequencing ◽

Cancer Associated Fibroblasts ◽

Single Cell Rna Sequencing ◽

Gene Expression Dynamics

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Intra-articular injection in the knee of adipose derived stromal cells (stromal vascular fraction) and platelet rich plasma for osteoarthritis

Journal of Translational Medicine ◽

10.1186/s12967-017-1242-4 ◽

2017 ◽

Vol 15 (1) ◽

Cited By ~ 53

Author(s):

Himanshu Bansal ◽

Kristin Comella ◽

Jerry Leon ◽

Poonam Verma ◽

Diwaker Agrawal ◽

...

Keyword(s):

Stromal Cells ◽

Platelet Rich Plasma ◽

Stromal Vascular Fraction ◽

Adipose Derived Stromal Cells

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Multilineage gene expression in human bone marrow stromal cells as evidenced by single-cell microarray analysis☆☆☆☆

Blood Cells Molecules and Diseases ◽

10.1016/s1079-9796(03)00150-5 ◽

2003 ◽

Vol 31 (2) ◽

pp. 268-285 ◽

Cited By ~ 56

Author(s):

Beerelli Seshi ◽

Sanjay Kumar ◽

Debra King

Keyword(s):

Gene Expression ◽

Bone Marrow ◽

Single Cell ◽

Microarray Analysis ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Marrow Stromal Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Cell Microarray

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Co-culture of functionally enriched cancer stem-like cells and cancer-associated fibroblasts for single-cell whole transcriptome analysis

Integrative Biology ◽

10.1093/intbio/zyz029 ◽

2019 ◽

Vol 11 (9) ◽

pp. 353-361 ◽

Cited By ~ 5

Author(s):

Yu-Chih Chen ◽

Seungwon Jung ◽

Zhixiong Zhang ◽

Max S Wicha ◽

Euisik Yoon

Keyword(s):

Breast Cancer ◽

Single Cell ◽

Transcriptome Analysis ◽

Stromal Cells ◽

Transcriptome Sequencing ◽

Functional Enrichment ◽

Cancer Associated Fibroblasts ◽

Tumor Initiation ◽

Whole Transcriptome Analysis ◽

Whole Transcriptome

Abstract Considerable evidence suggests that breast cancer development and metastasis are driven by cancer stem-like cells (CSCs). Due to their unique role in tumor initiation, the interaction between CSCs and stromal cells is especially critical. In this work, we developed a platform to reliably isolate single cells in suspension and grow single-cell-derived spheres for functional enrichment of CSCs. The platform also allows adherent culture of stromal cells for cancer-stromal interaction. As a proof of concept, we grew SUM149 breast cancer cells and successfully formed single-cell-derived spheres. Cancer-associated fibroblasts (CAFs) as stromal cells were found to significantly enhance the formation and growth of cancer spheres, indicating elevated tumor-initiation potential. After on-chip culture for 14 days, we retrieved single-cell derived spheres with and without CAF co-culture for single-cell transcriptome sequencing. Whole transcriptome analysis highlights that CAF co-culture can boost cancer stemness especially ALDHhigh CSCs and alter epithelial/mesenchymal status. Single-cell resolution allows identification of individual CSCs and investigation of cancer cellular heterogeneity. Incorporating whole transcriptome sequencing data with public patient database, we discovered novel genes associated with cancer-CAF interaction and critical to patient survival. The preliminary works demonstrated a reliable platform for enrichment of CSCs and studies of cancer-stromal interaction.

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